High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Discovering the genetic basis of cleft palate (Leslie)

腭裂（CP）是一种常见的颅面结构性出生缺陷，由腭（分隔口腔和鼻腔的结构）的不完全闭合引起，导致进食、言语和听力问题。CP占所有口面裂（OFC）的33%，或全球出生的1500名婴儿中约有1名。虽然CP通常与其他类型的口面裂（如唇裂或腭裂），CP是胚胎学和流行病学不同，提示一个独特的病因。一级亲属中CP复发的风险比群体风险高50倍以上，表明有很强的遗传成分。然而，一直缺乏CP的遗传研究。三个强有力的全基因组关联研究和荟萃分析显示，只有两个相关的基因座，这两个都没有占很大一部分的遗传在任何人群中的遗传。缺乏常见变异相关性表明CP的病因可能与其他先天性异常相似，如先天性心脏病，其通常由新生突变、遗传性罕见变异和拷贝数变异引起。我们建议通过在一个表型良好的多种族队列中对病例-父母三人组进行全基因组测序来阐明CP的遗传结构。此外，通过将这些数据与现有的唇腭裂和其他结构性出生缺陷的全基因组测序数据相结合，我们将能够识别与CP相关的常见途径或条件。为了实现这些目标，我们汇集了世界上最大的CP三人组，这些三人组来自我们多学科联盟的资源，该联盟汇集了OFC，测序，统计遗传学和风险变异的功能验证方面的专业知识。该项目有望迅速推进我们对CP遗传病因的理解，并将风险转移到家庭，并可能改善CP患者的诊断和治疗。

Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is commonly grouped with other types of orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct, suggesting a unique etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and copy number variation. We propose to elucidate the genetic architecture of CP by performing whole genome sequencing of case-parent trios in a well-phenotyped, multi-ethnic cohort. Further, by integrating these data with existing whole genome sequencing data for cleft lip and palate and other structural birth defects, we will be able to identify common pathways or conditions associated with CP. To accomplish these goals, we have assembled the largest cohort of CP trios in the world, drawn from the resources of our multidisciplinary consortium that brings together expertise on OFCs, sequencing, statistical genetics, and functional validation of risk variants. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.